KLINICKÉ ZKOUŠKY REFADORU PŘED REGISTRACÍ

Mitoxantrone

Mitoxantrone is an anthracenedione initially developed as an anti-neoplastic agent that reduces lymphocyte proliferation. Mitoxantrone intercalates into DNA strands, inducing strand breakage and inhibition of the DNA repair enzyme topoisomerase II. It is an immunosuppressive agent used as a second-line treatment for SPMS, primary relapsing multiple sclerosis and worsening RRMS. Mitoxantrone was approved for the treatment of SPMS based on the study by Hartung and colleagues [Hartung et al. 2002].

Several studies have shown it to be efficacious in reducing exacerbations and number of Gad+ lesions on MRI, and it seems to have effects on disease course up to 5 years after discontinuing therapy [Martinelli et al. 2009; Goodin et al. 2003]. Mitoxantrone is given as an intravenous infusion over 30 min every 3 months at 12 mg/m2 for a 2- to 3-year period with a maximum cumulative dose of 140 mg/m2. Common side effects include alopecia, nausea and vomiting, an increased risk of infection (particularly urinary and respiratory tracts infections) and amenorrhea. Mitoxantrone, though effective, remains second line due to its risk of two serious adverse effects that can occur at any time after the first dose is given. The first, acute leukemia has an incidence of approximately 0.81% [Marriott et al. 2010]. Regular monitoring of complete blood counts is recommended. Mitoxantrone can also cause decreased left ventricular ejection fraction (LVEF) and congestive heart failure at a rate of approximately 12% and 0.4%, respectively [Marriott et al. 2010]. To monitor cardiotoxicity, a baseline LVEF must be obtained and any patient with an ejection fraction less than 50% should not receive mitoxantrone. It was previously believed that cardiotoxicity could only occur with cumulative doses over 96-140 mg/m2; however, several reports of cardiotoxicity below this threshold have caused the FDA to recommend monitoring cardiac function before every infusion. The therapy must be discontinued if the LVEF ever falls below 50% or decreases by 10% [Martinelli et al. 2009].